The Framingham Osteoporosis Study (FOS) is a prospective study that is part of the Framingham Heart Study, one of the longest running cohort studies in the world. FOS involves participants from the Original Cohort (1948-present) and the Offspring Cohort (2nd generation and spouses). Both cohorts have comprehensive data about osteoporosis risk factors, as well as having stored DNA, relevant genotyping being performed by other groups, and large numbers of extended families in whom a genome wide scan has been carried out. We propose to continue the FOS. Our preliminary findings suggest that patterns of food consumption, dietary silicon and phosphoric acid intake have influences on bone mineral density (BMD). We will study these dietary factors as they relate to changes in BMD and fractures in both Cohorts. Findings from these studies may offer potential dietary approaches to preventing osteoporosis. We have recently completed a genome wide scan on some of the extended families in FOS who have completed BMD and quantitative calcaneal ultrasound (QUS), and found several loci with suggestive linkage. In some cases, loci differed between the BMD and QUS phenotypes. The results of this linkage analysis will be used to suggest potential gene candidates for association studies in addition to the ones that we will investigate in this project: interleukin-6 (IL-6), transforming growth factor beta (TGF-Beta), and estrogen receptors alpha and beta (ERa and ERBeta). We recently discovered that women with bone loss or low BMD have greater severity of vascular calcification, suggesting that the two processes may have a common etiology. We will test the hypothesis that this common etiology is related to estrogen and the estrogen receptors by using electron beam computed tomography to quantify vascular calcification, by measuring serum estradiol and sex-hormone binding globulin, and by genotyping women for ERa and ERBeta. This will advance our understanding of two of the most common chronic diseases affecting older persons.